FRI0328 PROFILING OF THE IMMUNE COMPARTMENT IN THE TISSUE ENVIRONMENT OF PSORIATIC ARTHRITIS USING RNASEQ

Abstract

Background:Psoriasis is a chronic inflammatory disease of the skin with a reported prevalence of 0.09-11.4% of the population (1). 1 in 4 psoriasis patients also have psoriatic arthritis (PsA) (2), with additional joint involvement that can be associated with significant morbidity. Despite its relative commonness, the aetiology of psoriasis is not well understood, and there is no cure for this disease. Additionally, up to 30% of PsA patients with active disease are recalcitrant to treatment. Thus it remains a prerogative to understand the immune mechanisms contributing to the development of the disease in order to inform strategies for novel therapies.Objectives:Our aim was to identify perturbations in local tissue immune networks that could contribute to the pathology of psoriasis and psoriatic arthritis. We hypothesise that psoriasis is driven by a disrupted tissue microenvironment, which then provides cues to a susceptible peripheral immune system to drive pathology. Thus as the first part of our study, we investigated the transcriptional profiles of normal and lesional skin.Methods:Skin punch biopsies were obtained from both lesional and morphologically normal skin of 4 PsA patients with active disease. CD45+ cells were isolated using magnetic enrichment for RNA purification and subsequent RNAseq. Differently expressed genes (DEG) were identified and pathway analysis performed using the integrated Differential Expression and Pathway (iDEP) analysis tool. Gene set enrichment analysis was performed using GSEA.Results:Transcriptomic analyses of skin revealed that lesional skin, compared to non-lesional sites, was enhanced for expression of genes associated with immune processes (including genes such as such asIL17A,FCN1, andCTLA4) anti-microbial responses (such asDEF4BAandS100A8) and immune cell chemotaxis (notablyCXCL13andSELPLG), suggesting a possible inflammatory response to skin microbiota. Interestingly, lesional skin showed a deficiency in expression of genes associated with tRNA metabolic processes (includingAARS,YARS, and other aminoacyl tRNA synthetases), suggesting a possible defect in protein translation. Similarly, pathway analysis revealed an enrichment in humoral immune response pathways in PsA lesional skin, and a comparative deficiency in RNA metabolic pathways.Conclusion:Our transcriptional approach provides a comprehensive overview of localised immunity in psoriasis and predicts intimate interactions with the peripheral immune system. Further studies are ongoing to uncover cell types involved, as well as parallels at other disease sites (joints). These findings will facilitate the identification of novel targets for treatment of PsA.